The Vector Void in Gene Therapy

Hodgson, Clague P.

doi:10.1038/nbt0395-222

Cited by 71 publications

(41 citation statements)

References 19 publications

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“…So far, no general protocol has been developed for the efficacious treatment of any particular genetic defect (2,3). One of the major problems shared in common by both approaches involves the delivery per se of the DNA or oligonucleotide into the cell, both in terms of intracellular delivery efficiencies and carrier-related toxicity.…”

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confidence: 99%

“…One of the major problems shared in common by both approaches involves the delivery per se of the DNA or oligonucleotide into the cell, both in terms of intracellular delivery efficiencies and carrier-related toxicity. The methods used so far rely on either viral systems (reconstituted virus particles, adenoviruses) (4-6) or chemicophysical technology (polymers, electroporation, calcium-phosphate precipitation, and liposomes) (3,7,8).…”

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confidence: 99%

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Novel pyridinium surfactants for efficient, nontoxic in vitro gene delivery

Woude

Wagenaar

Meekel

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

193

159

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Novel, double-chained pyridinium compounds have been developed that display highly efficient DNA transfection properties. The transfection efficiency of several of these compounds is enhanced by an order of magnitude, when compared with the transfection efficiency accomplished with the widely used cationic lipid system, lipofectin. Most importantly, the pyridinium compounds were found to be essentially nontoxic toward cells. Using various reporter genes, such as ␤-galactosidase and pNEO (a gene construct that renders cells resistent to antibiotic derivatives of neomycin like G418), we demonstrate that the enhanced efficiency relates to the fact that a relative higher number of cells in the population is transfected (Ϸ50% in the case of COS cells) by the pyridinium derivatives, whereas the delivery of DNA per cell is also enhanced. Furthermore, application of the pyridinium derivatives shows little cellular preference in their ability to transfect cells. By systematically modifying the structure of the pyridinium amphiphile, i.e., by changing either the headgroup structure or the alkyl chains, some insight was obtained that may lead to unraveling the mechanism of amphiphile-mediated transfection, and thus to protocols that further optimize the carrier properties of the amphiphile. Our results reveal that unsaturated alkyl chains enhance the transfection properties of the pyridinium-based amphiphiles. Preliminary experiments suggest that the structure-dependent improvement of transfection efficiency, when comparing pyridinium derivatives with lipofectin, likely relates to the mechanism of delivery rather than the packaging of the amphiphile͞DNA complex.

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confidence: 99%

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confidence: 99%

Novel pyridinium surfactants for efficient, nontoxic in vitro gene delivery

Woude

Wagenaar

Meekel

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

193

159

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“…Clinical use of retroviral vectors, methods are plasmids, although antisense oligonucleohowever, is hampered by safety issues. [1][2][3] A first concern tides are currently being tested as well. 8 Plasmid prepis the possibility of generating an infectious wild-type arations are simple, quick, safe, inexpensive and may be virus following a recombination event.…”

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confidence: 99%

Characterization of liposome-mediated gene delivery: expression, stability and pharmacokinetics of plasmid DNA

et al. 1997

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We have characterized a new synthetic gene delivery sysplasmid DNA could be detected in blood cells up to 1 h tem, termed DLS, which may be suitable for systemic gene after injection. Systemic administration of DLS-DNA therapy. DLS constitutes a lipopolyamine and a neutral yielded transgene expression in mouse tissues, such as in lipid and associated plasmid DNA in the formation of lamellung or liver. The ratio of DLS:DNA and the procedure used lar vesicles (DLS-DNA). The ratio of lipids and lipid to DNA to form DLS-DNA affected both the level and cellular as well as the method of preparation were optimized to specificity of expression of a luciferase reporter gene yield a high in vitro transfection efficiency compared with showing that in vitro transfection efficiency of DLS-DNA that previously reported for cationic lipid systems. DLSformulations cannot be easily extrapolated to an in vivo set-DNA showed a rapid cellular uptake and distribution in the ting. Optimization of the formulation of a DNA delivery syscytoplasmic and nuclear (especially in the nucleoli) comtem was critical to obtain a defined structure resulting in a partments as determined by laser-assisted confocal preparation with high reproducibility and stability, greater microscopy. There was little or no plasmid DNA degrahomogeneity of particle size and high efficacy following dation over a period of 20 min, relatively slow plasma clearsystemic gene transfer. In addition, the DLS system may ance, and effective and rapid cellular uptake of DLS-DNA be formulated for specific target tissues and may have a following intravenous administration in mice. Supercoiled wide range of applications for gene therapy.Keywords: gene transfer; liposomes; plasmid DNA; biodistribution; pharmacokinetics Synthetic gene transfer vectors are receiving increasingIntroduction study as an alternative to viral vectors since this strategy One of the main impediments to successful gene therapy appears to be safe. Potential methods of gene delivery is the generally poor efficiency of DNA delivery. Most that could be employed include the pneumatic DNA gene therapy efforts involve the use of retroviral vectors gun, 4 DNA-protein complexes 5 or lipidic particles. 6 The because of the usual efficient cell entry and stable intetypical genetic material delivered to target cells by these gration of the gene. Clinical use of retroviral vectors, methods are plasmids, although antisense oligonucleohowever, is hampered by safety issues.1-3 A first concern tides are currently being tested as well. 8 Plasmid prepis the possibility of generating an infectious wild-type arations are simple, quick, safe, inexpensive and may be virus following a recombination event. A second concern applied in combination with a synthetic carrier. Thereis the consequence of random integration of the viral fore, gene therapy by this means may be safe, durable sequence into the genome of the target cell which may and used as a drug-like therapy. The successful use of lead to a tumorigenic or a cytotoxic event. ...

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“…A fundamental challenge for gene therapy is the development of gene delivery vectors that target genes to the appropriate cells in the body for maximal therapeutic effect while minimizing vector toxicity (Hodgson, 1995;Kay, Liu, and Hoogerbrugge, 1997;Verma and Somia, 1997). One approach that takes advantage of the high transduction efficiency of animal viruses is to modify the tropism of a viral vector by attaching or engineering a targeting ligand onto the viral capsid or envelope (Goldman et al, 1997;Gu et al, 1999;McDonald et al, 1999;Rogers et al, 1998).…”

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confidence: 98%